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Clinical Outcomes of Stem Cell Transplants in Cancer Treatment
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Clinical Outcomes of Stem Cell Transplants in Cancer Treatment

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 25260

Special Issue Editor

Dr. Natalia Maximova

E-Mail Website
Guest Editor
Bone Marrow Transplant Unit, Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”, 34147 Trieste, Italy
Interests: pediatric allogeneic stem cell transplantation; hematological malignancies; inborn errors; cellular therapy; acute graft versus host disease; T cell-replete haploidentical graft; post-transplant cyclophosphamide

Special Issue Information

Dear Colleagues,

Hematopoietic stem cell transplantation (HSCT) has become a well-established treatment for various malignant and non-malignant disorders originating from the hematopoietic system. Improvements in transplantation techniques in recent years have led to a significant reduction in treatment-related complications. Importantly, this decline in mortality occurred despite the fact that older patients and patients with more comorbidities have been undergoing allogeneic HSCT in increasing numbers in recent decades. Areas of improvement have included changes in conditioning regimens, larger donor availability, better HLA-matching techniques and graft source manipulation, advanced techniques to detect minimal residual disease, post-transplant immunotherapy, progress in supportive care, graft-versus-host disease (GVHD) prophylaxis and therapy, and detection and treatment of subsequent infections. Successful allogeneic HSCT requires the development of an immune tolerance toward both the donor and host allogeneic antigens. Induction of an immune tolerance can prevent T-cell-mediated graft rejection and GVHD, which cause a severe pathology in HSCT recipients. Moreover, in hematologic malignancies, maintaining effective anti-tumor control while inducing a sustained immune tolerance is critical to survival following allogeneic HSCT.

GVHD remains one of the main complications after allogeneic HSCT. Despite very intensive research, no major advances in the management of GVHD have been made during the last two decades, except for post-transplant cyclophosphamide. An increased frequency of post-transplant cyclophosphamide for GVHD prophylaxis has allowed haploidentical HSCT to become a widely used approach because of its simplicity, low transplant-related mortality, and low incidence of severe GVHD, markedly expanding the pool of available donors.

Many challenges remain, particularly in minimizing primary disease relapse, which remains the major cause of HSCT failure. The implementation of immune-based therapies with use of chimeric antigen receptor (CAR) T-cells, bispecific antibodies, and checkpoint inhibitors could help to prevent treatment relapse after HSCT.

Dr. Natalia Maximova
Guest Editor

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Keywords

  • allogeneic hematopoietic stem cell transplantation
  • short-term complications
  • long-term outcomes
  • minimal residual disease
  • post-transplant immunotherapy
  • graft versus host disease
  • graft versus leukemia
  • post-transplant relapse

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Published Papers (8 papers)

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Research

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19 pages, 1979 KiB  
Article
Post-Transplant Cyclophosphamide and Tacrolimus—Mycophenolate Mofetil Combination Governs GVHD and Immunosuppression Need, Reducing Late Toxicities in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors
by Fabrizio Carnevale-Schianca, Daniela Caravelli, Susanna Gallo, Paolo Becco, Luca Paruzzo, Stefano Poletto, Alessandra Polo, Monica Mangioni, Milena Salierno, Massimo Berger, Rosanna Pessolano, Francesco Saglio, Daniela Gottardi, Delia Rota-Scalabrini, Giovanni Grignani, Marco Fizzotti, Ivana Ferrero, Pio Manlio Mirko Frascione, Lorenzo D’Ambrosio, Valentina Gaidano, Loretta Gammaitoni, Dario Sangiolo, Andrea Saglietto, Elena Vassallo, Alessandro Cignetti, Massimo Aglietta and Franca Fagioliadd Show full author list remove Hide full author list
J. Clin. Med. 2021, 10(6), 1173; https://doi.org/10.3390/jcm10061173 - 11 Mar 2021
Cited by 11 | Viewed by 4214
Abstract
Combined direct antineoplastic activity and the long-lasting immunological effects of allogeneic hematopoietic cell transplant (HCT) can cure many hematological malignancies, but broad adoption requires non-relapse mortality (NRM) rates and graft-versus-host disease (GVHD) control. Recently, posttransplant cyclophosphamide (PTCy) given after a bone marrow transplant [...] Read more.
Combined direct antineoplastic activity and the long-lasting immunological effects of allogeneic hematopoietic cell transplant (HCT) can cure many hematological malignancies, but broad adoption requires non-relapse mortality (NRM) rates and graft-versus-host disease (GVHD) control. Recently, posttransplant cyclophosphamide (PTCy) given after a bone marrow transplant significantly reduced GVHD-incidence, while PTCy given with tacrolimus/mofetil mycophenolate (T/MMF) showed activity following allogeneic peripheral blood stem cell transplantation (alloPBSCT). Here, we report the experience of a larger cohort (85 consecutive patients) and expanded follow-up period (03/2011–12/2019) with high-risk hematological malignancies who received alloPBSCT from Human-Leukocyte-Antigens HLA-matched unrelated/related donors. GVHD-prophylaxis was PTCy 50 mg/kg (days+3 and +4) combined with T/MMF (day+5 forward). All patients stopped MMF on day+28 with day+110 = median tacrolimus discontinuation. Cumulative incidences were 12% for acute and 7% for chronic GVHD- and no GVHD-attributed deaths. For surviving patients, the 12, 24, and 36-month probabilities of being off immunosuppression were 92, 96, and 96%, respectively. After a 36-month median follow-up, NRM was 4%; median event-free survival (EFS) and overall survival (OS) had yet to occur. One- and two-year chronic GVHD-EFS results were 57% (95% CI, 46–68%) and 53% (95% CI, 45–61%), respectively, with limited late infections and long-term organ toxicities. Disease relapse caused the most treatment failures (38% at 2 years), but low transplant toxicity allowed many patients (14/37, 38%) to receive donor lymphocyte infusions as a post-relapse strategy. We confirmed that PTCy+T/MMF treatment effectively prevented acute and chronic GVHD and limited NRM to unprecedented low rates without loss of disease control efficacy in an expanded patient cohort. This trial is registered at U.S. National Library of Medicine as #NCT02300571. Full article
(This article belongs to the Special Issue Clinical Outcomes of Stem Cell Transplants in Cancer Treatment)
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14 pages, 10255 KiB  
Article
Area-under-the-Curve-Based Mycophenolate Mofetil Dosage May Contribute to Decrease the Incidence of Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients
by Giorgia Carlone, Roberto Simeone, Massimo Baraldo, Alessandra Maestro, Davide Zanon, Egidio Barbi and Natalia Maximova
J. Clin. Med. 2021, 10(3), 406; https://doi.org/10.3390/jcm10030406 - 21 Jan 2021
Cited by 9 | Viewed by 2871
Abstract
Acute graft-versus-host disease (GvHD) remains the second leading cause of death, after disease relapse, in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The medical records of 112 pediatric patients who underwent allo-HSCT from matched unrelated and haploidentical donors were analyzed. Patients were [...] Read more.
Acute graft-versus-host disease (GvHD) remains the second leading cause of death, after disease relapse, in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The medical records of 112 pediatric patients who underwent allo-HSCT from matched unrelated and haploidentical donors were analyzed. Patients were divided into two groups, according to the GvHD prophylactic regimen used. In the control group, GvHD prophylaxis consisted of cyclosporine A (CsA) and methotrexate (MTX) or CsA and mycophenolate mofetil (MMF) at a standard daily dose of 30 mg/kg. All subjects in the study group received tacrolimus (FK506) and MMF. In this group, MMF was subjected to therapeutic drug monitoring (TDM) through mycophenolic acid (MPA) area under the curve AUC0–12. We found a statistically significant difference in both overall acute GvHD (p < 0.0001) and overall chronic GvHD (p < 0.05) incidence between the study and the control group. The initial daily MMF dose and the age at transplant in the study group proved to be inversely correlated (r = −0.523, p < 0.0001). The children under six years of age required a significantly higher daily MMF dose (p < 0.008). This study showed that pharmacological monitoring of MPA AUC0–12 concentration allowed a reduction in the incidence of acute and chronic GvHD. MMF showed age-dependent pharmacokinetics due to greater drug clearance in younger children. Full article
(This article belongs to the Special Issue Clinical Outcomes of Stem Cell Transplants in Cancer Treatment)
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15 pages, 1563 KiB  
Article
Risk Factors and Outcome of C. difficile Infection after Hematopoietic Stem Cell Transplantation
by Chiara Rosignoli, Giuseppe Petruzzellis, Vera Radici, Gabriele Facchin, Marco Girgenti, Rossella Stella, Miriam Isola, Martalisa Battista, Alessandra Sperotto, Antonella Geromin, Michela Cerno, Alessandra Arzese, Paola Deias, Carlo Tascini, Renato Fanin and Francesca Patriarca
J. Clin. Med. 2020, 9(11), 3673; https://doi.org/10.3390/jcm9113673 - 16 Nov 2020
Cited by 5 | Viewed by 2670
Abstract
Patients who undergo hematopoietic stem cell transplants (HSCT) are at major risk of C. difficile (CD) infection (CDI), the most common cause of nosocomial diarrhea. We conducted a retrospective study, which enrolled 481 patients who underwent autologous (220) or allogeneic HSCT (261) in [...] Read more.
Patients who undergo hematopoietic stem cell transplants (HSCT) are at major risk of C. difficile (CD) infection (CDI), the most common cause of nosocomial diarrhea. We conducted a retrospective study, which enrolled 481 patients who underwent autologous (220) or allogeneic HSCT (261) in a 5-year period, with the aim of identifying the incidence, risk factors and outcome of CDI between the start of conditioning and 100 days after HSCT. The overall cumulative incidence of CDI based upon clinical evidence was 5.4% (95% CI, 3.7% to 7.8%), without any significant difference between the two types of procedures. The median time between HSCT and CDI diagnosis was 12 days. Out of 26 patients, 19 (73%) with clinical and symptomatic evidence of CDI were positive also for enzymatic or molecular detection of toxigenic CD; in particular, in 5 out of 26 patients (19%) CD binary toxin was also detected. CDI diagnoses significantly increased in the period 2018–2019, since the introduction in the microbiology lab unit of the two-step diagnostic test based on GDH immunoenzymatic detection and toxin B/binary toxin/027 ribotype detection by real-time PCR. Via multivariate analysis, abdominal surgery within 10 years before HSCT (p = 0.002), antibiotic therapy within two months before HSCT (p = 0.000), HCV infection (p = 0.023) and occurrence of bacterial or fungal infections up to 100 days after HSCT (p = 0.003) were significantly associated with a higher risk of CDI development. The 26 patients were treated with first-line vancomycin (24) or fidaxomicine (2) and only 2 patients needed a second-line treatment, due to the persistence of stool positivity. No significant relationship was identified between CDI and the development of acute graft versus host disease (GVHD) after allogeneic HSCT. At a median follow-up of 25 months (range 1–65), the cumulative incidence of transplant related mortality (TRM) was 16.6% (95% CI 11.7% to 22.4%) and the 3-year overall survival (OS) was 67.0% (95% CI 61.9% to 71.6%). The development of CDI had no significant impact on TRM and OS, which were significantly impaired in the multivariate analysis by gastrointestinal and urogenital comorbidities, severe GVHD, previous infections or hospitalization within two months before HSCT, active disease at transplant and occurrence of infections after HSCT. We conclude that 20% of all episodes of diarrhea occurring up to 100 days after HSCT were related to toxigenic CD infection. Patients with a history of previous abdominal surgery or HCV infection, or those who had received broad spectrum parenteral antibacterial therapy were at major risk for CDI development. CDIs were successfully treated with vancomycin or fidaxomicin after auto-HSCT as well as after allo-HSCT. Full article
(This article belongs to the Special Issue Clinical Outcomes of Stem Cell Transplants in Cancer Treatment)
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13 pages, 2391 KiB  
Article
Dynamic Changes of Inhibitory Killer-Immunoglobulin-Like Receptors on NK Cells after Allogeneic Hematopoietic Stem Cell Transplantation: An Initial Study
by Tereza Dekojová, Lucie Houdová, Jiří Fatka, Pavel Pitule, Pavel Ostašov, Valentina S. Caputo, Hana Gmucová, Daniel Lysák, Pavel Jindra and Monika Holubová
J. Clin. Med. 2020, 9(11), 3502; https://doi.org/10.3390/jcm9113502 - 29 Oct 2020
Cited by 4 | Viewed by 2501
Abstract
Killer-immunoglobulin-like receptors (KIRs) are critical natural killer (NK) cell regulators. The expression of KIRs is a dynamic process influenced by many factors. Their ligands—HLA(Human Leukocyte Antigen) class I molecules—are expressed on all nucleated cells that keep NK cells under control. In hematopoietic stem [...] Read more.
Killer-immunoglobulin-like receptors (KIRs) are critical natural killer (NK) cell regulators. The expression of KIRs is a dynamic process influenced by many factors. Their ligands—HLA(Human Leukocyte Antigen) class I molecules—are expressed on all nucleated cells that keep NK cells under control. In hematopoietic stem cell transplantation (HSCT), NK cells play an essential role in relapse protection. In the presented pilot study, we characterized the dynamic expression of inhibitory KIRS (iKIRs), which protect cells against untoward lysis, in donors and patients during the first three months after HSCT using flow cytometry. The expression of all iKIRs was highly variable and sometimes correlated with patients’ clinical presentation and therapy regiment. Cyclophosphamide (Cy) in the graft-versus-host disease (GvHD) prevention protocol downregulated KIR2DL1 to just 25% of the original donor value, and the FEAM (Fludarabine + Etoposid + Ara-C + Melphalan) conditioning protocol reduced KIR2DL3. In lymphoid neoplasms, there was a slightly increased KIR2DL3 expression compared to myeloid malignancies. Additionally, we showed that the ex vivo activation of NK cells did not alter the level of iKIRs. Our study shows the influence of pre- and post-transplantation protocols on iKIR expression on the surface of NK cells and the importance of monitoring their cell surface. Full article
(This article belongs to the Special Issue Clinical Outcomes of Stem Cell Transplants in Cancer Treatment)
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13 pages, 710 KiB  
Article
Allogeneic Stem Cell Transplantation in Relapsed/Refractory Multiple Myeloma Treatment: Is It Still Relevant?
by Hyunkyung Park, Ja Min Byun, Sung-Soo Yoon, Youngil Koh, Dong-Yeop Shin, Junshik Hong and Inho Kim
J. Clin. Med. 2020, 9(8), 2354; https://doi.org/10.3390/jcm9082354 - 23 Jul 2020
Cited by 1 | Viewed by 2456
Abstract
Background: Despite offering an attractive option, the role of allogeneic stem cell transplantation (alloSCT) for treatment of multiple myeloma (MM) remains unclear. Methods: Recognizing the paucity of data in the Asian population, we retrospectively evaluated the outcomes of 24 patients (median age 52) [...] Read more.
Background: Despite offering an attractive option, the role of allogeneic stem cell transplantation (alloSCT) for treatment of multiple myeloma (MM) remains unclear. Methods: Recognizing the paucity of data in the Asian population, we retrospectively evaluated the outcomes of 24 patients (median age 52) undergoing alloSCT between April 2003 and November 2017. Results: The median time from diagnosis to alloSCT was 39.4 months. The majority of the patients (70.8%) underwent alloSCT followed by reduced intensity conditioning regimens after a median of five lines of therapy. Among 24 patients, 15 patients (62.5%) had a high-risk MM feature. The two-year relapse-free survival (RFS) and overall survival (OS) of the total patients were 29.2 ± 9.3% and 44.3 ± 10.3%, respectively. Patients who were treated with less chemotherapy lines (<5) before alloSCT had a prolonged RFS and OS. All patients (seven patients) who received a myeloablative conditioning regimen had high-risk features, but two out of seven patients showed long-term survival without lasting sequelae. Nine patients (37.5%) experienced non-relapse mortality (NRM) within one year after alloSCT (the one-year cumulative incidence of NRM was 38.3 ± 10.1%). Conclusion: AlloSCT can still be implemented as effective salvage option in the treatment of relapsed/refractory high-risk MM. The optimal timing of alloSCT remains to be determined. Full article
(This article belongs to the Special Issue Clinical Outcomes of Stem Cell Transplants in Cancer Treatment)
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12 pages, 2464 KiB  
Article
Pentaglobin® Efficacy in Reducing the Incidence of Sepsis and Transplant-Related Mortality in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation: A Retrospective Study
by Giorgia Carlone, Lucio Torelli, Alessandra Maestro, Davide Zanon, Egidio Barbi and Natalia Maximova
J. Clin. Med. 2020, 9(5), 1592; https://doi.org/10.3390/jcm9051592 - 24 May 2020
Cited by 8 | Viewed by 3999
Abstract
The 12-month mortality rate in patients undergoing hematopoietic stem cell transplantation (HSCT) remains high, especially with respect to transplant-related mortality (TRM), which includes mortality due to infection complications through the aplasia phase. The aim of this study was to determine whether the administration [...] Read more.
The 12-month mortality rate in patients undergoing hematopoietic stem cell transplantation (HSCT) remains high, especially with respect to transplant-related mortality (TRM), which includes mortality due to infection complications through the aplasia phase. The aim of this study was to determine whether the administration of Pentaglobin® could decrease TRM by lowering sepsis onset or weakening sepsis through the aplasia phase. One hundred and ninety-nine pediatric patients who had undergone HSCT were enrolled in our retrospective study. The patients were divided into two groups: the Pentaglobin group, which had received Pentaglobin® in addition to the standard antibiotic treatment protocol established for the aplasia phase, and the Control group, which received only the standard treatment. As compared to the control group outcome, Pentaglobin® led to a significant decrease in the days of temperature increase (p < 0.001) and a reduced infection-related mortality rate (p = 0.04). In addition, the number of antibiotics used to control infections, and the number of antibiotic therapy changes needed following first-line drug failure, were significantly lowered in the Pentaglobin group as compared to the control group (p < 0.0001). With respect to the onset of new infections following the primary infection detected, the Pentaglobin group showed a significant reduction for bacterial events, as compared to the control group (p < 0.03). Pentaglobin® use in patients undergoing HSCT seems to produce a significant decrease in infection-associated TRM rate. Full article
(This article belongs to the Special Issue Clinical Outcomes of Stem Cell Transplants in Cancer Treatment)
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Review

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17 pages, 247 KiB  
Review
Haploidentical Stem Cell Transplantation in Lymphomas—Expectations and Pitfalls
by Jacopo Mariotti, Stefania Bramanti, Armando Santoro and Luca Castagna
J. Clin. Med. 2020, 9(11), 3589; https://doi.org/10.3390/jcm9113589 - 7 Nov 2020
Cited by 4 | Viewed by 2386
Abstract
T-cell replete Haploidentical stem cell transplantation (Haplo-SCT) with Post-transplant cyclophosphamide (PT-Cy) is an emerging therapeutic option for patients with advanced relapsed or refractory lymphoma. The feasibility of this platform is supported by several retrospective studies showing a toxicity profile that is improved relative [...] Read more.
T-cell replete Haploidentical stem cell transplantation (Haplo-SCT) with Post-transplant cyclophosphamide (PT-Cy) is an emerging therapeutic option for patients with advanced relapsed or refractory lymphoma. The feasibility of this platform is supported by several retrospective studies showing a toxicity profile that is improved relative to umbilical cord blood and mismatched unrelated donor (UD) transplant and comparable to matched unrelated donor transplant. In particular, cumulative incidence of chronic graft-versus-host disease (GVHD) is reduced after Haplo-SCT relative to UD and matched related donor (MRD) transplant thanks to PT-Cy employed as GVHD prophylaxis. This achievement, together with a similar incidence of acute GVHD and disease relapse, results in a promising advantage of Haplo-SCT in terms of relapse-free/GVHD free survival. Unmet needs of the Haplo-SCT platform are represented by the persistence of a not negligible rate of non-relapse mortality, especially due to infections and disease relapse. Future efforts are warranted in order to reduce life-threatening infections and to employ Halo-SCT with PT-Cy as a platform to build new immunotherapeutic strategies. Full article
(This article belongs to the Special Issue Clinical Outcomes of Stem Cell Transplants in Cancer Treatment)
22 pages, 355 KiB  
Review
Allogeneic Transplantation in Multiple Myeloma—Does It Still Have a Place?
by Gösta Gahrton, Simona Iacobelli, Laurent Garderet, Ibrahim Yakoub-Agha and Stefan Schönland
J. Clin. Med. 2020, 9(7), 2180; https://doi.org/10.3390/jcm9072180 - 10 Jul 2020
Cited by 15 | Viewed by 3316
Abstract
Novel drugs have improved survival for patients with multiple myeloma in recent years. However, the disease is still fatal. Allogeneic stem cell transplantation (Allo) has proven to cure some patients with the disease, but its role is controversial due to relatively high transplant-related [...] Read more.
Novel drugs have improved survival for patients with multiple myeloma in recent years. However, the disease is still fatal. Allogeneic stem cell transplantation (Allo) has proven to cure some patients with the disease, but its role is controversial due to relatively high transplant-related toxicity and mortality (nonrelapse mortality, NRM). Using nonmyeloablative reduced-intensity conditioning (RIC), both toxicity and NRM can be reduced, and RICAllo is, therefore, an option for subgroups of patients. Upfront tandem autologous/RICAllo (Auto/RICAllo) was shown to be superior to single Auto or tandem Auto/Auto in both progression-free (PFS) and overall survival (OS) in two prospective studies with long-term follow-up, while three similarly designed studies did not detect a difference. A recent update of pooled patient data from four of these studies showed significantly superior PFS and OS with Auto/RICAllo. Importantly, none of these studies showed inferior results with Auto/RICAllo in patients less than 70 years of age. Auto/RICAllo appears to overcome some poor risk cytogenetic markers. Encouraging results have also been seen in treatment of relapsed patients. Combining Allo with new proteasome inhibitors and immunomodulatory drugs may further improve results. Other encouraging new cell therapies such as with CAR T-cells, NK- and CAR NK-cells may well have a place in combination with RICAllo. Such studies are warranted. Full article
(This article belongs to the Special Issue Clinical Outcomes of Stem Cell Transplants in Cancer Treatment)
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